From Petri Dish to Patient: Bioavailability Estimation and Mechanism of Action for Antimicrobial and Immunomodulatory Natural Products

Abstract

The new era of multidrug resistance of pathogens against frontline antibiotics has compromised the immense therapeutic gains of the ‘golden age,’ stimulating a resurgence in antimicrobial research focused on antimicrobial and immunomodulatory components of botanical, fungal or microbial origin. While much valuable information has been amassed on the potency of crude extracts and, indeed, purified compounds there are too many reports that uncritically extrapolate observed in vitro activity to presumed ingestive and/or topical therapeutic value, particularly in the discipline of ethnopharmacology. Thus, natural product researchers would benefit from a basic pharmacokinetic and pharmacodynamic understanding. Furthermore, therapeutic success of complex mixtures or single components derived therefrom is not always proportionate to their MIC values, since immunomodulation can be the dominant mechanism of action. Researchers often fail to acknowledge this, particularly when ‘null’ activity is observed. In this review we introduce the most up to date theories of oral and topical bioavailability including the metabolic processes affecting xenobiotic biotransformation before and after drugs reach the site of their action in the body. We briefly examine the common methodologies employed in antimicrobial, immunomodulatory and pharmacokinetic research. Importantly, we emphasize the contribution of synergies and/or antagonisms in complex mixtures as they affect absorptive processes in the body and sometimes potentiate activity. Strictly in the context of natural product research, it is important to acknowledge the potential for chemotypic variation within important medicinal plants. Furthermore, polar head space and rotatable bonds give a priori indications of the likelihood of bioavailability of active metabolites. Considering this and other relatively simple chemical insights, we hope to provide the basis for a more rigorous scientific assessment, enabling researchers to predict the likelihood that observed in vitro anti-infective activity will translate to in vivo outcomes in a therapeutic context. We give worked examples of tentative pharmacokinetic assessment of some well-known medicinal plants.

White Sage (Salvia apiana)–a Ritual and Medicinal Plant of the Chaparral: Plant Characteristics in Comparison with Other Salvia Species

“…In such a case, therapeutic doses necessary to achieve contact inhibition may result in dangerously high systemic concentrations and possible toxic effects. Antimicrobial activity in vivo of essential oils should be considered mainly for topical therapies since MIC concentrations cannot be realistically achieved in the plasma [89].…”

Carvacrol, a Plant Metabolite Targeting Viral Protease (Mpro) and ACE2 in Host Cells Can Be a Possible Candidate for COVID-19

“…Learning from the discovery of Tamiflu ® , phytochemicals, and natural products with antiviral, anti-inflammatory, and immunomodulatory properties should be investigated for the prevention and cure of SARS-CoV-2 infections. Among all these therapeutic approaches, natural products, mainly essential oils (EOs) have drawn much interest because of their robust use as anti-inflammatory, immunomodulator, and antioxidant as well as a source of novel antimicrobial, anti-inflammatory, and immunomodulator agents ( Allegra et al, 2014 ; Sadgrove and Jones, 2019 ). EOs are well recognized for their strong antiviral, anti-inflammatory, and immunomodulatory activities ( de Lavor et al, 2018 ; Asif et al, 2020 ; Gandhi et al, 2020 ).…”

In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors

“…More likely, the larval innate immune system got triggered by the decreased amount of capsule, which led to an increase in phagocytosis rate and decrease in virulence, as observed before (Preston and Dockrell, 2008). This sort of therapy is considered a good adjuvant to the conventional antimicrobial therapy in the light of the battle against antimicrobial resistance (Sadgrove and Jones, 2019). Lastly, while the in vivo model rendered multiple statistical differences between treated groups and untreated controls, this effect was not seen in in vitro adherence to and phagocytosis in a macrophage cell line.…”